Intro: Welcome to Pediatric Voices, Duke Children's podcast about kids health care. Now here's our host, Dr. Angelo Milazzo.

Angelo Milazzo, MD (Host): Hello and welcome to Pediatric Voices, a podcast that dives deeply into conversation with the people who make up the Duke Children's Health Care team. I'm Dr. Angelo Milazzo. I'm a Pediatric Cardiologist and a Professor of Pediatrics here at Duke Children's and one of the hosts of this podcast. I'm here to bring you expert insights about timely topics in children's health.

On this episode of Pediatric Voices, let's look at neonatal brain health and the developing field of fetal neurology. I've mentioned it previously, but again, as a reminder, I'm a Pediatric Cardiologist, so a lot of what I do in medicine involves taking care of newborns and young children with complex life threatening heart disease.

And fortunately, we have the technology to treat these children in terms of offering both medical and surgical care and addressing their cardiac issues. But in recent years, my colleagues and I have become more and more invested in understanding the impact of early cardiac disease on the neurologic health of our patients.

For example, here at Duke Children's, we've developed a comprehensive programmatic approach, and we now run all of our newborn patients with heart disease through a very thorough and ongoing neurologic evaluation process. We have a specialized program in our clinics, which follows these children closely through the earliest stages of life. And it's a joint effort among many different kinds of specialists; people who are interested in these issues, including neonatologists, cardiologists, and of course, child neurologists.

So that's just one example of an area within pediatrics where early development, early brain health, early neurologic health is very important in my field as a Pediatric Cardiologist. Today we're going to take a broader look, however, and I'm very lucky I have the perfect expert today to shed light on the issue of neonatal neurology and to introduce us to the exciting developments in the emerging science and medicine of Fetal Neurology.

Today, I'll be talking with my colleague, Dr. Jeffrey Russ. Dr. Russ is an Assistant Professor of Pediatrics in the Duke University School of Medicine here in sunny Durham, North Carolina. He joined our faculty after training at the Weill Cornell Medical Center and the Rockefeller University in New York, my hometown, and at the University of California at San Francisco.

He leads clinical care here in the areas of fetal and neonatal neurology. He is greatly invested in research as well. His fields of study include brain development, neurogenetics, perinatal brain injury, and he is committed to the development of new therapies to impact neuro developmental injury during the very earliest stages of life.

Welcome Dr. Russ. Jeff, it is a tremendous pleasure to have you on the Pediatric Voices show.

Jeff Russ, MD, PhD: Thanks, Dr. Milazzo. I'm really happy to be here.

Host: Jeff, let's start with your origin story, as I like to phrase it. How did you first get interested and involved in children's health? And then how did you get interested in your particular field within child neurology?

Jeff Russ, MD, PhD: Yeah, it's sort of funny because neonatal neurology in particular is a very niche area of expertise; and it's not like I just woke up one day and said, Oh, I'm going to do neonatal neurology. I think for a very long time, even as far back as high school, I was always interested in neuroscience and trying to understand how the brain works.

To me, that's one of the most interesting frontiers in science right now. And so with that as sort of an overarching guiding interest, as I went through my training, I'll say it really came down to mentors that I had along the way and, as a little bit of an aside, when I'm often providing career advice to others, I always talk about the importance of mentorship.

And I do that because I think really good mentors that I've had have really shaped where I ended up. So I remember, for example, being in my early medical school classes, learning about embryology, and thinking, well, this all sounds pretty dry. It's just a bunch of different genes and cells dividing, I want to really understand brain circuitry. But my PhD advisor, who worked in spinal cord development was such a good mentor who taught me a lot about just the field of neuroscience and neurodevelopment, and over time I started to really see myself as a neurodevelopmental neuroscientist, and I started to appreciate all of the intricacy of building these neural circuits. So, where I sort of came into things thinking I wanted to understand how neural circuits work; I've really started to believe in the idea that in order to do that, you have to understand how they're built from the beginning. And from there, pediatric neurology and then neonatal neurology was just such a natural fit.

The medical pathophysiology, just was so fascinating in trying to link that with my scientific interests. And hopefully putting those two things together to start to understand neonatal brain pathology and start to develop therapies for some of the conditions I see.

Host: Jeff, I love that answer. And in particular, I love it for two reasons. You know, it aligns with a lot of what I've heard from my prior guests. First, you had a very early formative experience, which seems to be very common among pediatricians and probably among physicians in general, and that early experience guided your path in life and in your career.

And then second, you mentioned the importance of a mentor and mentorship. And I've said it before on the show that medicine is one of the last great apprenticeship systems. You know, we find these mentors, these inspirational role models, and more often than not, the way our career develops is often, in the path of someone who's gone before us. So again, I, really love that answer. And I always say one of the great things about the show is learning about how my colleagues came to be who they are. It's very exciting.

Jeff Russ, MD, PhD: Maybe I'll just add real quick, I often say that a good mentor can really make you love something that you maybe didn't expect that you were going to enjoy so much and a less than ideal mentor, can often make you struggle with something that you thought you were really going to enjoy. It really makes a huge difference.

Host: Absolutely. It's so impactful in terms of how our careers are shaped. So I couldn't agree with you more. So, you know, we're here today to discuss fetal neurology, and these associated areas in medicine that you both do research in and provide clinical care. And as I said at the outset of the show, as a fellow traveler, someone who manages conditions prenatally and perinatally, I can absolutely appreciate the impact of this work. And I'm personally fascinated by the work you do. So tell me, if you're introducing this subject to our audience, where do you begin, how would you lay out the terms of the conversation for our listeners?

Jeff Russ, MD, PhD: One of the most important things about fetal and neonatal brain health that I just have come to appreciate more and more and more the longer I've been in this field is how rapidly the brain changes from early embryo development all the way through to infancy and honestly, even through, early childhood and adolescence and even young adulthood. There's so much rapid brain development and I've really come to appreciate the stage specific nature of this. So, each trimester of fetal development is so different, and a premature neonate's brain and a term neonate's brain are also very different, and starting to understand and appreciate the nuance that you bring to each of those different stages is so important. So maybe one thing that's helpful to listeners is just to clarify some of these terms, in particular, the fetus refers to the neonate before they're born and, pregnancy is divided into three trimesters. And so when I'm talking about fetal neurology, I'm sort of talking about the development of the baby's brain before birth over those three trimesters. And then a neonate is right after the baby is born. And really technically, the neonatal period refers to about the first month of life, after which they're called an infant. So if I'm using those terms, and sometimes they get used a little bit interchangeably, I really sort of divide things in my head, between fetal neurology before the baby's born and neonatal neurology after the baby's born in that first month of life.

Host: That's really helpful for you to spec it out that way. I think often we take these terms for granted, but that elucidation is going to be really helpful for folks who are listening to this conversation today. So now that you've kind of set the terms of engagement, can you describe some of the conditions, some of the problems that you're dealing with both in prenatal neurology and in neonatal neurology?

Jeff Russ, MD, PhD: Yeah, I would say prenatal neurology is based a lot around structural brain malformations. So, a pregnant person gets an ultrasound, often the 18 week anatomy scan, where the obstetrician will go in detail and look at a variety of different anatomic structures, has the baby's hands formed the right way? Are there the right number of fingers? Do the kidneys look okay? Does the heart look okay? Are there any congenital heart malformations, for example. And so oftentimes, if an obstetrician catches some kind of concern in the developing fetus's brain, they'll refer them to me to try to understand a little bit better what these things may mean, and especially to try to help a family begin to understand what the prognosis might be. So, some of these conditions are fairly rare, and if you haven't been exposed to them, you may not have even heard of them. Fetal neurology has its own whole vocabulary, that takes a little while to get familiar with, but I would say it's often divided into has your nervous system closed?

So our nervous systems are all a tube that divides into lots of different complex parts, but has that tube fully closed into a cylinder? Do each of the parts form the way that they're supposed to, and then have all of the neurons started to arrange in the way that we expect them to and send their projections and nerves and the directions that we expect them to.

And if any of those parts go awry for a broad variety of different reasons, we may see that on the ultrasound as some kind of large structural brain malformation. So a lot of what goes into fetal neurology is trying to take that information and help families contextualize it, to understand what the developmental prognosis of their baby may end up being. That's on the fetal side.

Neonatal neurology oftentimes is dealing with the ramifications of things that we've found on fetal ultrasound, but I would say it also encompasses a category of perinatal brain injury. So babies that are born very premature, their brains are very delicate, the blood vessels in their brain are very delicate, and that can lead to a variety of different brain injuries; especially if those kids end up getting sick for other reasons. Premature babies are just so delicate as you can imagine, and even getting something like an infection puts the body into an inflammatory state and can lead to brain injury. But those perinatal brain injuries that we see in premature neonates are also very different from what we might see in a term neonate. So, term neonates, somewhat commonly wind up with a condition that we call neonatal encephalopathy. And even though that has a fancy term, it really just means the baby's brain's not functioning the way that we expect it to. The baby doesn't seem like they're acting right. And often that can be caused for a wide variety of different reasons, but one of the more common ones is that there may have been some period of decreased blood flow or decreased oxygen to the baby's brain. And so, that can lead to things like seizures and motor delays, cerebral palsy, developmental disorders. And so that's kind of the spectrum of what we treat, in fetal and neonatal neurology.

Host: So it sounds like Jeff, first of all, it's a fairly broad family of conditions that you're dealing with. You're dealing with several distinct phases of early childhood. You talked about the prenatal conditions. You talked about premature neonates, so babies that are born earlier than expected. And then you talked about term neonates, babies that are born essentially on time. And there are conditions in each of those three ranges of age that can have significant impact on the development of the nervous system. And again, we're talking about more than just the brain. We're talking about the spinal cord and the associated nerves of the body. Does that capture the general tenor of what you're trying to get across?

Jeff Russ, MD, PhD: Yeah, that's correct. You know, again, I think one of the big take home points is just how, stage specific the types of diseases can be. And while I'm very interested in sort of understanding at a high level of detail, the genetics, the circuitry, the way that different neurons change as a result of these things, I would say broadly, all of these conditions converge on symptoms like, seizures, cerebral palsy, which means difficulty with movement as a result of something that happened around the time of birth. Or developmental delay. So, having difficulty learning to speak, learning to walk, learning to feed yourself, and that can be a sort of a wide spectrum. So everything from the initial diagnosis of these conditions to the longer term management for kids with these conditions.

Host: Awesome. Now we're getting to a really important area because now we're talking about what are those things that become evident to families and caretakers that could lead them to seek your help. So thinking first about your prenatal patients. So, you know, you have a woman who's pregnant who may have a concern about the neurologic health of her fetus. Perhaps something has come up in an obstetrical evaluation or perinatal evaluation. What are the warning signs? What are the things that could come up during pregnancy that could lead a woman to seek consultation with you and your team?

Jeff Russ, MD, PhD: I would say most commonly, it's an obstetric concern on an ultrasound. So somebody notices that the baby's brain doesn't seem like it's forming in exactly the correct way, and has some concern. And the obstetrician will then often refer that patient to see me and start to talk about what this means. That said, I think some of the practical take home points, especially for anyone who's pregnant who could be worried about something like this, you know, I don't want to scare anybody or sort of drive anybody to seek care, out of a high level of concern, but some of the things would be a really strong family history of a condition, might cause someone to sort of seek prenatal care from a neurologist. Decreased fetal movement. So, mom notices that suddenly the baby's not moving as much. Sometimes that can be a sign of distress for the fetus also, if, the mom notices any symptoms or conditions that are concerning to her.

So, abdominal pain or vaginal bleeding, things that might be a sign that there's an issue with the pregnancy, I would often say, start with the obstetrician; but, they often know that if there's any concern about how a patient's pregnancy may affect the fetus's brain, they'll often have a low threshold to refer them to see me.

Host: Jeff, what about families where there are other children that may have neurologic illness. And you know, this comes up a lot in my practice with cardiovascular illness, but I'm curious. So if a pregnant woman has another child who has epilepsy or who has autism, would those be reasons to seek prenatal neurologic evaluation of the fetus?

Jeff Russ, MD, PhD: The first thing I would say is that there's never a bad reason to seek prenatal neurologic evaluation. I'm happy to see any patient who has a concern and wants to discuss. When I think about a family where there's an older sibling who has a certain condition, we do often wonder about could there be something genetically mediated, and by that I mean something that's being passed down through the family, obviously unintentionally, that could affect subsequent pregnancies?

And sometimes the answer is yes, and sometimes no. I think something like autism is so complex that we still don't fully understand all of the genetics behind autism. That may be harder, though I'm certainly happy to talk a family about what those risks might be. But a more concretely defined genetic condition. So I know, for example, another episode of Pediatric Voices had Dr. Jennifer Cohen, who's a pediatric geneticist who I work closely with. And if she knows of a family who has Gaucher's disease for example, or Pompe disease, some of these disorders that we know are a result of a single gene that may be being passed down through a family, I would probably be on more high alert to start to screen for those things in subsequent pregnancies and would be happy to talk to families about that.

Host: That's a really fantastic point you made. And yes, as you alluded to, Dr. Cohen was a previous guest on the show and I had the privilege of talking to her about her work. And I think if nothing else, it highlights the interoperability of us. You know, we here at Duke Children's, as in all children's hospitals across the country and the world, you know, we work as a team and often it takes many of us in a multidisciplinary fashion working on a problem to really bring to bear a full set of solutions.

So that's one of the things that has me always excited about being here is I get to collaborate as you're collaborating with Jennifer. I certainly do similar collaborations in my practice and that's part of the fun of being here. So I love that answer. So Jeff, we talked a little bit about signs, symptoms, concerns for pregnant women who may seek prenatal evaluation.

Let's go to the other end of your spectrum now. Let's think about the term newborn, the newborn who maybe goes home from the hospital as expected. You mentioned some of these signs and symptoms before, but could you go into a little bit more detail about what a family could see in an otherwise, know, ostensibly healthy newborn? What could raise a warning flag that they need to think about a full term neonatal neurologic problem?

 Thank

Jeff Russ, MD, PhD: Yeah, when I think about the most common reasons that postnatal kids, so kids who are born, have gone home from the nursery, wind up in my clinic; I would say it falls probably into kind of three main categories. The first is the kid's not meeting developmental milestones. So this is something that parents are screening for. This is something that the pediatrician is screening for. We know that generally kids should be attaining skills at certain ages. So, again, these are sort of general terms, but, you know, sitting by about 6 months, walking by about 1 year, those types of things. And every pediatrics appointment, especially early in life, is evaluating, is a kid meeting those milestones. And if it starts to become clear that a baby may not be meeting those milestones, that would definitely be a valid reason to come see a pediatric neurologist, especially someone with neonatal neurology expertise like myself, to discuss why that might be and screen for certain causes for that. That's Category 1. I would say Category 2 would be what we refer to in neurology as a focal deficit. So, basically something really obvious on the body that a kid isn't doing correctly. So, not moving an arm appropriately or not moving a leg appropriately would be a very obvious example. Not seeming to track faces, so concerns about the visual system, not startling to noises, or not regarding voices, concerns about hearing and speech development. So basically something that we would expect a kid to do that they're not doing that you can see in a pretty obvious way. And that would definitely be a reason to come see a pediatric neurologist.

Host: So Jeff, when you consider variations in development, you know, not all kids sit up at the same time, not all kids crawl at the same time, not all kids walk at the same time. How does a family distinguish between what could be just variability in the way we develop or a real problem? Is there a way for them to do that without your help or should they err on the side of caution and reach out?

Jeff Russ, MD, PhD: I think that I would always say, I'm happy to see even a healthy kid and to reassure a family, I think your kid is healthy. That's actually a great appointment for me. I'm happy to do that. So I would say in general, to be willing to see a neurologist, even if you're not sure whether the concern warrants rising to the level of neurologic evaluation.

That said, red flags that I tend to think about are not sort of anchoring and fixating so much on just one thing, but what's the broader context? Is there sort of a broader picture that suggests there may be more at play? What I don't want someone to take home from this is my kid started sitting up at 7 months instead of 6 months.

Should I be worried about that? Probably not. If they've otherwise had a healthy prenatal and postnatal period, and they're otherwise doing well, and they just sort of aren't sitting as quickly as their older sibling did, 99 times out of 100, they're probably a healthy kid. Though I'm still happy to see them and say so. But I would say if the context seems to suggest that they're missing multiple milestones. They frequently aren't doing things that we would sort of expect them to do. And also, if the pediatrician is starting to have some concerns, those would be reasons I think to initiate care with a neurologist.

And part of the reason that I have a low threshold to say come see a neurologist is that we also know that the earlier that we intervene, the better that kids can do. So, rather than wait a year and see how a kid is doing, do they continue to miss milestones? I would just rather see them early on and address something if it needs to be addressed.

Host: So let's talk about those things that you can do. What do interventions look like, whether it's premature baby or full term neonate. What kinds of tools do you have at your disposal as a pediatric neurologist to actually impact these conditions?

Jeff Russ, MD, PhD: I would say right out of the gates that one big misconception about pediatric neurology is that we can't do anything for our patients. There's sort of a phrase that gets thrown around in med school that neurologists are all diagnose and adios. And I don't think that's true at all. Obviously I would like to see us get to a point where we can really pinpoint, oh, this is exactly what's wrong in a child's brain. It's these neurons and these circuits, and here's a medicine that directly addresses those. I would love to get to that point. We're not there, but that doesn't mean that we can't do things for kids with neurologic disorders. So, I would say seizures are a very common result of different kinds of genetic disorders or brain injury. And one of the things that's my bread and butter in a pediatric neurology clinic is treating seizures. So I think that's a very direct way that we can intervene. A kid has seizures, we recognize it on an electroencephalogram, or EEG, we have plenty of seizure medications that are safe in kids, with a very low side effect profile, and oftentimes, we can get those seizures under control, and that'll help developmental outcomes.

So that's a pretty straightforward thing. For something like developmental delay, the treatments that we have available may be less directly specific to the condition, but they're still helpful nevertheless. So a lot of times what that looks like is a category of services called early intervention services; physical therapy, occupational therapy, speech therapy, feeding therapy, vision therapy. And studies have shown, there's literature to support that the earlier and more extensively a kid who has developmental risks gets plugged into services like this, the better they do. So I often tell families hey, your kid actually is doing way better than I expected. They look great. They may not need physical therapy pretty soon, but I would still rather overdo it than underdo it at this very early, developmentally plastic stage. And we know that the earlier and more extensively we do those types of therapies, the better outcomes that kids have.

Host: I love that answer. You know, it connects back to something I said at the outset that we've come to appreciate as cardiologists, and that is early intervention for children who may be at risk of neurologic deficit because they have cardiac disease, and there is definitely a relationship between the two, early intervention is key.

And you almost cannot start too early. So we've actually backed that process up all the way to the very initial stages of life. And that's been a really exciting change, really exciting development.

Jeff Russ, MD, PhD: Well, and I would piggyback on that by saying, first off, I agree with you. I think that is a very exciting development. And I would say as neonatal neurology has evolved over the years, we've really come to appreciate how early you can intervene in postnatal life, and I would say now, sort of the next challenge on the horizon and something I'm very interested in is, how do you start to intervene in prenatal life? So I think plenty of people would very appropriately say, intervening on day of life zero or day of life one is really early. We're catching kids early. We're doing something early. And yet, for certain genetic conditions, metabolic conditions, structural brain malformations, so much brain development is happening in utero, while the fetus is still inside of the mom's uterus; that the neonatal period itself may already be a little bit too late for some of these kids.

And so now there's a big question of, how can we intervene in utero? And to me, that's a really exciting next step.

Host: I agree. It's also, again, as another symmetry between our fields; it's the same kind of question we're asking in pediatric cardiovascular medicine. What can we do to impact cardiac disease and cardiac development before the baby is born? Because there may be a tremendous opportunity and that's sort of the cutting edge, the vanguard of some of the work that's being done in prenatal cardiology. So yeah, I'm with you. Incredibly exciting. So Jeff, anyone who reviews today's show notes in any kind of detail is going to see that you are a scientist as well as a medical doctor. Like some of our previous guests, you have both an MD and a PhD after your name. I'm always in awe of people who have taken that road because it's incredibly challenging, and it's wonderful to work with physician scientists here at Duke Children's. Can you tell us a little bit about your research and what you've been able to achieve in your work here?

Jeff Russ, MD, PhD: So, I would say I'm still early in my career, although, as you pointed out, what that really means for an MD PhD is, I'm 15 years into training and sort of finally getting my lab, the Russ lab underway and launched, and when I think about what the mission of my scientific research is; I divide it into two categories. The first is trying to understand the pathology of these different genetic brain disorders in much more detail. So right now I can look at imaging of a baby's brain and say this broad region of the brain is affected. But what we can't quite do yet is start to drill down into this type of neuron is affected, this circuit is affected, and here's what that means. And so the first part of my mission is to just try to use some really cutting edge techniques to try to understand how specific types of neurons and circuits are affected in some of these conditions that we've talked about today. And then the second part is to try to figure out what to do about that therapeutically. So, I'm very interested in looking for new tools that we can use that would be safe to apply to a fetus in utero, still during pregnancy; to try to ameliorate some of these genetic disorders and structural brain malformations. One tool in particular is an RNA based tool that my research mentor, Dr. Josh Wong in Duke Neurobiology developed that I hope could one day be used to introduce into a baby's brain to help start to rewire some of the circuits, that may be underlying the brain disorders that that baby has. Now that's a long way away. There's a lot of steps between where we're at now and turning this into a real therapy. But I'd like to keep an eye out for those types of tools and start to try to adapt them as a treatment for some of these disorders.

Host: And that's a great example of what's so exciting when we have physician scientists at the helm of these initiatives. You're able to understand these things through your work in the lab, with your colleagues in the pure sciences, and then you can translate that. You can see the clinical problems and understand where those innovations can actually be put into practice to help people. And that's one of the amazing promises of an institution like ours here at Duke Children's. So, fantastic answer. I really appreciate that. So, Jeff, I want to take you out on a question that I like to ask everyone. I put you on the spot a little bit, so I apologize in advance, but if you were not Dr. Jeff Ross, MD, PhD, and not a child neurologist and a researcher, what would you have been? Who would you be?

Jeff Russ, MD, PhD: It's fun to think about. And maybe on some of my more challenging days in science and medicine, I fantasize a little bit about what other career paths might I have taken. Obviously, I'm glad I took this one. But the answer to that is that probably, I would open a cocktail bar, and try to do custom cocktails.

I just think that would be fun and creative. And if not that, I think I would probably try to be a rock guitarist.

Host: Jeff, I could easily see you being both of those things. Those are great answers.

Jeff Russ, MD, PhD: Maybe in another chapter, maybe, a couple of years from now, I'll, come back and tell you about my cocktail bar.

Host: Absolutely. Again, like I've said many times, learning stuff about the people I work with every day for me is the greatest benefit of this show. So thank you very much. I appreciate that. Jeff, I want to thank you again for being a guest on the podcast. I loved having you on the show. I absolutely hope that you will come back and talk to us again about other topics in child neurology. This was an amazing experience for me and I learned a ton of new information today. Thank you so much.

Jeff Russ, MD, PhD: Absolutely. It was a lot of fun to participate in this. Thanks for having me.

Angelo Milazzo, MD (Host): Pediatric Voices is brought to you by Duke Children's Hospital and the Department of Pediatrics at the Duke University Medical Center here in sunny Durham, North Carolina. Pediatric Voices was created by my friend, Dr. Richard Chung, and by me, Dr. Angelo Milazzo. Courtney Sparrow is brand new to our team, so welcome, Courtney.

She is keeping us on track and helping us stay organized. Debbie Taylor is a friend of the show and has been with us since the beginning. She is providing a huge ongoing assist. We love working with our great friends at Dr. Podcasting. They produce the show and they are amazing folks to work with. Thanks to our Chair of Pediatrics here at Duke, Dr. Anne Reed, and her leadership team for their continued support of the show. You can find our show and please hit the subscribe button wherever you find your favorite podcasts. That includes Apple Podcasts, Google Podcasts, TuneIn, iHeartRadio, Spotify, and now you can find us at Pandora as well. Very exciting.

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